Background
The concept of arrhythmogenic cardiomyopathy (AC) has evolved over the last 25 years, resulting in a variety of synonyms for this disease. Over the years, the disease has been referred to as arrhythmogenic right ventricular dysplasia/cardiomyopathy, owing to its predilection for the right ventricle. However, is it become increasingly common to refer to it as arrhythmogenic cardiomyopathy (AC) in recognition of primarily left ventricular and biventricular forms of the disease. Gradually, the concept emerged that the right ventricle was infiltrated by fat and scar and that aneurysms were not uniformly present. Electrocardiographic and imaging studies expanded the phenotypic profile of the disease, which was consistently characterized by ventricular tachyarrhythmias and clinically resembled cardiomyopathy (“arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)” or “arrhythmogenic right ventricular cardiomyopathy (ARVC)”). The etiologic significance of the fat portion of the infiltrates was debated, and eventually it was agreed that the fibrotic portion of the pathologic process was indeed the
sine qua non for diagnosis. Finally, as further autopsy studies have emerged, as well as more sensitive imaging, such as cardiac CT and MR, it has been recognized that left ventricular involvement is typical and possibly more common than the right ventricular changes.
1,2,3
Etiology
Between 30% and 50% of patients with AC have a family history of cardiomyopathy, and pathogenic mutations in genes encoding cardiac proteins are identified in 46% of patients.
4In addition to genetic causes, other possible etiologies for AC include a congenital malformation (dysplasia), now considered unlikely, and a healed myocarditis. The presence of inflammation in a large proportion of autopsy cases, as well as clinical documentation of myocarditis progressing to AC,
5,6 is in support of an inflammatory etiology for at least some cases and was once considered the likely cause.
7,8 It is likely that there is a “two-hit” phenomenon, namely, that myocarditis (viral or other types) progresses to AC if there is a predisposing genetic basis, such as those involving the desmosome or ryanodine receptor, affecting cardiomyocytes diffusely.
Genetics
Genetic studies based on animal models, rare families with coincidental skin lesions, and family studies of isolated cardiomyopathy have led to the discovery of mutations in genes related to the desmosome. These include plakophilin-2 (
PKP2), desmoplakin (
DSP), and desmoglein-2
(
DSG2).
9,10 Many distinct mutations have been described for each, including over 25 for
PKP2 alone.
11 Up to 40% of all mutations are unique or “private,” limited to a single proband or family.
4 Other desmosomal genes mutated in AC include plakoglobin (
JUP) and desmocollin-2 (
DSC2).
9Mutations unrelated to desmosomal proteins have also been identified in families of patients with AC as well as series of unrelated probands. These include the cardiac ryanodine receptor (
RYR2),
12 transmembrane protein 43 encoding gene (
TMEM43), phospholamban (
PLN),
13,14,15 transforming growth factor beta-3 (
TGFβ3), αT-catenin (
CTNNA3), lamin A/C (
LMNA), desmin (
DES), and titin (
TTN).
9Linkage analyses have identified loci not containing the above genes, and no causative genes have been identified in these regions yet. These loci (14q12-q22, 2q32.1-q32.3, 10p14-p
12 and 10q22.3) and most of the identified genes listed above form the basis for a numbering system for AC from 1 to 12 (Online Mendelian Inheritance in Man, www.omim.org) (
Table 158.1).
10The reported strong association between AC and mutations in desmosomal proteins may be somewhat biased. Firstly, series of unrelated patients only looked for mutations in desmosomal proteins, ignoring others,
4 leading to their inclusion as a major diagnostic criterion for the disease thereby boosting their frequency in AC (
Table 158.2). Only recently have pathogenic nondesmosomal mutations been sought and found in a large proportion of unrelated patients with AC.
12 Secondly, desmosomal mutations were evaluated only recently in series of unrelated patients with other types of cardiomyopathy, which has led to the discovery of a high rate of desmosomal mutations in diseases other than AC, such as dilated cardiomyopathy. 20 Third and most importantly, pathologic confirmation of the diagnosis is only rarely accomplished by biopsy, and the clinical criteria are somewhat nonspecific, making genotypic/phenotypic correlation difficult. Autopsy series of AC with high throughput analysis of cardiomyopathic genes are not yet available, and cardiac imaging studies are not at this time sophisticated enough to make a reliable diagnosis of AC.
